Safety and clinical activity of target-preserving anti-CTLA-4 antibody ONC-392 as monotherapy in NSCLC patients who progressed on PD(L)1-targeted immunotherapy.
Authors: Kai He, David Paul Carbone, Meredith McKean, Rama Balaraman, Satish Shah, Edward Arrowsmith, Julio Antonio Peguero, Rohit Joshi, Aiwu Ruth He, Adriana Milillo, John Turner Hamm, Mark Gregory Goldstein, Zihai Li, Yang Liu, Pan Zheng, Tianhong Li
Journal: Journal of Clinical Oncology (2023)

9024 Background: PD-1 or PD-L1 inhibitors have transformed clinical care of NSCLC patients. However, many patients may develop primary or secondary resistant to PD-(L)1 inhibitors. The marketed anti-CTLA-4 mAbs are ineffective as monotherapy for NSCLC. ONC-392 is a novel target-preserving anti-CTLA-4 antibodies that confers immunotherapeutic effect by selective depletion of regulatory T cells (Treg) in the tumor microenvironment. Preclinical studies show that ONC-392 is more effective and less toxic for immunotherapy than other clinically used anti-CTLA-4 antibodies. In first-in-human study in patients with advanced solid cancer, the recommended Phase 2 dose (RP2D) for ONC-392 monotherapy was established as 10 mg/kg. In this study, we tested safety and clinical activities of ONC-392 in NSCLC patients who progressed on PD(L)1-targeted therapy. Methods: Anti-PD-(L)1 resistant NSCLC patients were enrolled as parts of PRESERVE-001 studies (NCT04140526) expansion cohort Part C Arm I and treated with 2 cycles of 10 mg/kg, followed by 6 mg/kg, q3w, ONC-392 by IV infusion. Safety was evaluated based on treatment emergent and treatment-related adverse events, while efficacy was evaluated by investigators using RECIST1.1 criteria. Results: As of December 18, 2022, 33 NSCLC patients have received at least one dose of ONC-392 at 10 mg/kg. The median age is 66 yrs (range 43 - 89 yr), 61% male. 61% were non-squamous cell carcinoma and 39% were squamous cell carcinoma. 27% are ECOG score 0 and 73% were ECOG score 1. The median prior treatment was 2 cycles (range 1 to 4). The average ONC-392 treatment period was 3.5 cycles (range 1 to 13 cycles). Overall, the patients with TRAE in grade 3 or above is 33% (11/33), including diarrhea/colitis (3, 9%), AST/ALT increase or hepatitis (3, 9%), muscular weakness (2, 6%), nephritis (1, 3%), adrenal insufficiency (1, 3%). Due to pace of enrollment, efficacy data are available in 22 patients. 6 of 22 evaluable patients have partial response and 12 patients have stable disease per RECIST 1.1, resulting in a response rate of 27% and disease control rate of 82% among evaluable patients. The median follow-up period for all patients is 5.8 months and 8.6 months for 20 alive patients (range 2.9 to 14.1 months). The estimated 6- and 12-month overall survival (OS) rates were 65% and 55%. Median OS has not reached. Conclusions: Overall, ONC-392 monotherapy with 10 mg/kg is safe and tolerable. Onc-392 monotherapy has showed encouraging anti-tumor activity in IO-resistant NSCLC when compared with historical data. Based on these encouraging data, we have initiated a Phase 3 study testing ONC-392 monotherapy among NSCLC who progressed on PD(L)1-targeting immunotherapy (NCT05671510). Clinical trial information: NCT04140526 .